From Fight or Flight to Freak and Fry

An Argument for PTSD as the Pathological Expression of HPA & ANS Excitotoxic / Allostatic Overload of the Limbic System: Too Much of a Good Thing is Not a Good Thing.

Neurobiology of the Stress Response: Contribution of the Sympathetic Nervous System To the Neuroimmune Axis in Traumatic Injury

Molina, Patricia E
Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, Louisiana

Shock: Injury, Inflammation, and Sepsis: Laboratory and Clinical Approaches, Vol. 24, No. 1, July 2005, pp 3-10

http://journals.lww.com/shockjournal/fulltext/2005/07000/neurobiology_of_the_stress_response__contribution.2.aspx

RG: I have run across other material in the PTSD literature suggesting that overproduction and/or over-long production of pro-inflammatory cytokines is a principle factor in the excitotoxicty of dendritic receptor sites in the limbic system of PTSD sufferers. I am utilizing this state-of-the-art-in-2005 description of what was known at that time about the functions of the hypothalamo-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) as a platform to introduce what I have learned elsewhere about excitotoxity to provide an explanation of the micro-neurobiology of PTSD as I have been able to see it in the computer-adied tomography of PTSD sufferers. I would like to invite any and all who have superior grasp of the topic to weigh in with comments, factual corrections, etc. I am indebted to Dr. Molina and to Lippincott, Williams and Williams for making the article available for this usage. RG, December 2011.

Abstract

Acute injury produces an immediate activation of neuroendocrine mechanisms aimed at restoring hemodynamic and metabolic counter-regulatory responses. These counter-regulatory responses are mediated by the systemic and tissue-localized release of neuroendocrine-signaling molecules known to affect immune function. This has led to the recognition of the importance of neuroendocrine-immune modulation during acute injury as well as throughout the recovery period. The period immediately after acute injury is characterized by upregulation of proinflammatory cytokine expression leading to a later period of generalized immunosuppression. The course and progression of the host recovery from traumatic injury and the integrity of its response to a secondary challenge is directly related to the effective control of the immediate proinflammatory responses to the initial insult. Among the neuroendocrine mechanisms involved in restoring homeostasis, the sympathetic nervous system plays a central role in mediating acute counter-regulatory stress responses to injury. In addition to its recognized cardiovascular, hemodynamic, and metabolic effects, the neurotransmitters released by the sympathetic nervous system have been shown to affect immune function through specific adrenergic receptor-mediated pathways. In turn, cells of the immune system and their products have been shown to influence peripheral and central neurotransmission, leading to the conceptualization of a bidirectional neuroimmune communication system. The reflex activation of this bidirectonal neuroimmune pathway in response to injury, integrated with the parasympathetic nervous system, and opioid and glucocorticoid pathways responsible for orchestrating the counterregulatory stress response, results in dynamic regulation of host defense mechanisms vital for immune competence and tissue repair. This review provides the biological framework for the integration of our understanding of the neuroendocrine mechanisms involved in mediating the stress response and their role in modulating immune function during and after traumatic injury.

INTRODUCTION

Despite considerable advancement in the development of treatment modalities, our understanding of the processes involved in control of inflammatory responses is incomplete (in 2005). Recently, the importance of neuroendocrine mechanisms has gained recognition, leading to the redefinition of our traditional views of the factors controlling inflammatory responses. Because uncontrolled as well as impaired inflammatory responses can lead to deleterious outcomes, it is imperative to develop the appropriate knowledge base and conceptualization of the control mechanisms involved. Inflammatory responses are not exclusive to chronic or infectious conditions, but have also been identified after acute stress such as that resulting from traumatic injury. Among the etiological factors directly involved in triggering the pro-inflammatory response associated with traumatic injury are tissue hypo-perfusion, hypoxia, infection, and burn (1, 2).

The contribution of neuroendocrine mechanisms to the dynamic regulation of the magnitude and tissue specificity of inflammatory responses has been recognized by several investigators. Considerable attention has been given to the effectiveness of parasympathetic nerve stimulation in suppressing the magnitude of the pro-inflammatory response, leading to coining of the term inflammatory reflex (3). Interestingly, the stress response to injury is associated with suppressed parasympathetic nervous system activity and prevalence of the activation of the other arm of the autonomic nervous system-the sympathetic nervous system. Furthermore, systemic and tissue release of norepinephrine and epinephrine, the principal neurotransmitters of the sympathetic nervous system, exert marked cellular responses on cells of the immune system. Thus, as we increase our understanding of the role of neuronal pathways in modulating the inflammatory response, it is important to integrate the role and contribution of both arms of the autonomic nervous system in the regulation of the inflammatory responses.

Dissecting the relative contribution of the sympathetic nervous system to modulation of immune responses during traumatic injury requires an analysis of conditions under which this arm of the autonomic nervous system is activated: its anatomical interactions with immune competent cells and the functional consequences of this interaction as they affect the regulation of the host response. We begin by providing an overview of the neurobiology of the stress response, and we go on to describe how the organism responds to stress and the neuro-circuitry that is involved, as well as how the efferent autonomic and neuro-endocrine pathways involved in mediating the peripheral responses to stress modulate immune function.

CONDITIONS UNDER WHICH THE SYMPATHETIC NERVOUS SYSTEM IS LIKELY TO BE INVOLVED IN CONTROL OF INFLAMMATION

Alterations in the environment or acute insults to an individual that require adaptation involve the synchronized interaction of multiple neuronal and endocrine pathways geared at restoring homeostasis and ensuring the fundamental survival, growth, and reproductive functions of the host (Fig. 1). The integrated hemodynamic, metabolic, behavioral, and immune responses that allow adaptation of the host are referred to as the stress response (4). Central to the integration of this reflex neuro-endocrine response are the hypothalamo-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS). Their activation in response to stress is centrally integrated, particularly at the level of the periventricular nucleus of the hypothalamus and the locus ceruleus. In parallel to activation of the SNS response, the parasympathetic nervous system tone responsible for vegetative functions is suppressed. Several additional neuro-endocrine pathways are simultaneously activated, which, in turn, form redundant and feedback circuits (feed-forward or negative feedback), contributing to a synchronized cascade of efferent neuro-endocrine signals targeted to increase the host's ability to respond to the stress signal. Despite the multiple and intricate interconnected pathways, the two pathways at the core of the stress system wiring are the HPA axis and the SNS system.

The core function of the HPA and SNS pathways is central to the host's adaptation to acute challenges by ensuring energy substrate mobilization, cardiovascular and hemodynamic compensation, increasing awareness, and subsequently by contributing to host immune function and tissue repair (5). Signals sent to other brain regions, including those that are not directly involved in the immediate restoration of vital functions during acute stress, affect additional behavioral and physiological responses such as sleep, growth, reproduction, and mood. Although the short-term activation of these stress response mechanisms is vital by providing substrate availability to sustain increased metabolic demands of the individual, prolonged duration and increased magnitude of their activity leads to deleterious effects on metabolism (6), immune function (7), reproduction (8), and cardiovascular function (9). Similarly deleterious is the impaired activation or lack of responsiveness of the HPA and autonomic nervous systems, as in the case of the critically ill patient. Thus, the overall appropriate and controlled activation and termination of the neuroendocrine responses that mediate the necessary physiological functions involved in maintaining and restoring homeostasis in the event of illness, trauma, surgery, or fasting are of critical importance.

Using hemorrhagic shock as a model of acute stress, one can dissect the role of the SNS and identify its role as a key component of the neuroendocrine response to stress (Fig. 1). The hemorrhage-induced decreases in mean arterial blood pressure lead to decreased stretch of the baroreceptors in the carotid sinus and aortic arch this decreased firing from baroreceptors initiates afferent signals to the CNS. These afferent signals include visceral peptidergic projections (to oxytocin neurons in the hypothalamus), and signals from the nucleus tractus solitarius relayed via A1 (noradrenergic) and C1 (adrenergic) cells of the ventrolateral medulla (targeting hypothalamic arginine vasopressin and corticotrophin-releasing hormone [CRH] neurons). Additional afferent signals to the hypothalamus are relayed through neurotransmitters other than catecholamines, including glutamate and γ-amino butyric acid. The integration of these afferent signals occurs predominantly at the level of the periventricular nucleus (10), triggering a cascade of intra- and extra-hypothalamic neurochemical events. These signals are relayed via classical transmitters, as well as numerous neuropeptides, including CRH, opioids, neuropeptide Y and galanin, and gaseous neuromodulators like nitric oxide and carbon monoxide, many of which are co-localized with classical transmitters and may act in concert with them at the level of individual PVN neurons. Clearly, multiple neurochemical pathways are simultaneously activated and integrated during the compensatory response to acute blood loss.

In parallel to central relay signals dictating the CNS response to acute stress, descending autonomic visceromotor (11) (brainstem and spinal projections) cell groups (12) are activated as well (Fig. 1). The resulting efferent or descending signals are primarily directed to restoring hemodynamic and metabolic homeostasis, ensuring adequate perfusion and oxygenation of tissues, as well as energy substrate mobilization to sustain the increased demands of the organism during this fight or flight response. These descending projections control heart rate and blood pressure (13) and make contact with sympathetic and parasympathetic preganglionic neurons in the intermediolateral nucleus of the thoracic and lumbar spinal cord. In addition, these neuronal pathways are capable of stimulating cells of the immune system directly through neurotransmitter release in the parenchyma of lymphoid organs (14), and indirectly through neurotransmitter and hormonal release into the circulation. Several lines of evidence indicate that these neurotransmitters and neuromodulators exert significant effects on the inflammatory/immune response, affecting the ability of the host to repair tissue damage and produce an adequate host defense from infections. Thus, descending autonomic neuronal pathways control vital hemodynamic and metabolic functions while also modulating several aspects of the immune system.

THE CNS SIGNALS THE IMMUNE SYSTEM THROUGH NEURONAL AND HORMONAL PATHWAYS

Catecholamines are among the neurotransmitters that affect immune responses humorally through circulating adrenal-derived epinephrine, as well as locally through neuronal release of norepinephrine. Studies have provided anatomical evidence of CNS-lymphoid organ connection through autonomic and sensory fibers in immune tissues such as the bone marrow, thymus, spleen, and lymph nodes (Fig. 2). This sympathetic innervation of lymphoid organs is found across species and has been confirmed by specific immunohistochemistry for tyrosine hydroxylase. In the bone marrow, myelinated and nonmyelinated fibers with immunoreactivity to tyrosine hydroxylase, vasoactive intestinal peptide, and neuropeptide Y are distributed with vascular plexuses where they may influence hemopoiesis and cell migration (15). In the lungs, noradrenergic nerve fibers supply tracheobronchial smooth muscle and glands. In addition, nerve fibers have also been demonstrated throughout the different compartments of bronchus-associated lymphoid tissue, e.g., under the epithelium, in the smooth muscle layer, along the vasculature, and between immune cells of bronchus-associated lymphoid tissue parenchyma, forming close contacts with mast cells, cells of the macrophage/monocyte lineage, and/or other lymphoid cells (16). In the thymus, noradrenergic nerve fibers have been localized in the subcapsular, cortical, and corticomedullary regions, associated with blood vessels and intralobular septa, occasionally branching into the cortical parenchyma where they reach close proximity to thymocytes.

Among the organs that have received the most attention because of the technical feasibility of surgical and chemical manipulation to investigate the role of neuroimmunomodulation is the spleen. Fluorescence histochemistry has demonstrated noradrenergic nerve fibers entering the spleen with the splenic artery and then further distributing with the central artery, with the capsular and trabecular systems, and into the parenchyma where they distribute among T lymphocytes and along a macrophage zone at the marginal sinus. The origin of sympathetic neural innervation in rat spleen is predominantly the superior mesenteric/celiac ganglion. More recent and sophisticated techniques have allowed visualization of noradrenergic fiber distribution into B cell follicles, particularly during development. Thus, T and B lymphocytes as well as macrophages have been identified to be located at sites adjacent to tyrosine hydroxylase-positive nerve fibers, where they are exposed to neuronal norepinephrine release (17). Similar patterns of innervation have been described for cervical, mesenteric, and popliteal lymph nodes, as well as Peyer's patch and lymphoid tissue associated with the appendix. Noradrenergic nerves have been visualized entering the lymph nodes at the hilus with the vasculature and distributed throughout the medullary cords among mixed populations of lymphocytes and macrophages, and in the subcapsular region. These fibers contribute to innervation of the paracortical and cortical regions, regions abundant with T lymphocytes. In addition to the innate distribution of neuronal fibers in close proximity with cells of the immune system, the local production of neuropeptides by cells of the immune system has also been recognized as a mechanism through which neuroimmunomodulation of localized inflammation can take place (18). The enzymatic capacity of immune cells to synthesize, store, and release neurotransmitters like norepinephrine has added an autocrine neuroimmune mechanism not considered in this review, but worth further investigation.

Thus, in lymphoid tissues, lymphocytes and macrophages are located at sites adjacent to neuronal fibers, exposing them to local release of neuropeptides forming synaptic-like neuroimmune interactions, allowing modulation of localized inflammatory responses through direct neural release and humoral neuroendocrine mediators. The local release of neuroendocrine mediators coupled with specific receptor expression in immune cells establishes a functional neuroimmune connection capable of modulating various responses, including cytokine production, neutrophil chemotaxis, phagocytosis, and reactive oxygen species production and release.

WHAT IS THE FUNCTIONAL SIGNIFICANCE OF THESE NEUROENDOCRINE-IMMUNE INTERACTIONS?

The functional significance of neuroimmune synaptic interactions has been demonstrated by several studies. Catecholamines and adrenergic agonists in particular have been demonstrated to exert important regulatory functions on macrophages as well as on B and T lymphocyte cytokine production, proliferation, and antibody secretion (19). In vivo studies have shown that catecholamines affect dendritic cell function, enhancing myelopoiesis and suppressing lymphopoiesis through specific adrenergic receptor mechanisms (20) (but just as insufficient length or amount of catecholamine delivery would fail to adequately enhance myelopoiesis and suppress lymphopoiesis, catecholamine delivery over too long a timespan will induce excitotoxicity at the dendritic entry points and “blow the system.” Overproduction or over-extended production of cytokines is not desirable). In vitro studies have demonstrated that catecholamines inhibit lipopolysaccharide (LPS)-induced macrophage production of tumor necrosis factor (TNF) (21), interleukin (IL)-12 (22), and macrophage inhibitory protein 1α (23) and enhance LPS-stimulated release of IL-10 (24), while suppressing nitrite production (25). The contribution of adrenergic regulation of cytokine production is also evident by the increased TNF-α production by peritoneal macrophages obtained from sympathectomized mice (26).

The conclusions reached by some studies appear to be conflictive, part of which can be explained by differential effects mediated by the specific receptor subtypes, as well as by the differential cellular response. Catecholamines act on their target cells through binding to cell surface adrenergic receptors. (This is pretty likely where “excitotoxicity” occurs as the result of prolonged hammering upstream on the sympathetic branch of the ANS.) Reports indicate that α- and β-adrenergic receptors are expressed in immune cells, with β-adrenergic receptors having a wider expression in these cells (27). β-Adrenergic receptors belong to the family of G protein-coupled receptors that when activated by ligand binding, lead to elevation of intracellular cAMP and activation of protein kinase A. Like other ligand-mediated cAMP elevations, catecholamines suppress TNF, IL-1, and IL-6, and enhance IL-10 production via this mechanism. In contrast, results from in vitro experiments indicate that catecholamine effects mediated through α-adrenergic receptors can enhance TNF message and IL-12 expression (28). Given that expression of β-adrenergic receptors predominates in cells of the immune system, adrenergic effects would favor an anti-inflammatory effect over one of proinflammation. However, overall, it would be an in vivo systemic response that would provide more relevant information on the contribution of the sympathetic nervous system to control of inflammation.

The overall suppressive effect of norepinephrine in proinflammatory mediator release has been demonstrated in studies conducted in our laboratory in which alveolar- and spleen-derived macrophages isolated from naive rats were challenged with LPS in the presence of norepinephrine (10 nM). In this setting, adrenergic stimulation resulted in marked suppression of LPS-induced TNF release from both cell types. Other laboratories have observed similar anti-inflammatory effects of norepinephrine on astrocyte activation and production of TNF (29). Additional mechanisms to that of suppression of cytokine production were identified in those studies. Removal of norepinephrine resulted in enhanced amyloid-induced inflammation (bingo; as per the previous note) attributed to decreased intracellular IκB. Overall, noradrenergic depletion potentiated β-amyloid-induced cortical inflammation and neuronal cell death (30) (which is precisely what happens the fight-or-flight response is maintained for too long and heads into freak and fry), providing evidence that the role of noradrenergic innervation is not limited to control of an acute inflammatory response.

The functional effects of catecholamines on cells of the immune system have been confirmed in healthy human volunteers (31). Furthermore, the relevance of this control mechanism and the implications for its dysregulation have been demonstrated by the rapid systemic release of IL-10 and the high incidence of infection in patients with sympathetic storm from acute accidental or iatrogenic brain trauma (32). (I’ll suggest here that the same sort of sympathetic storm occurs as the result of cognitive priming of the HPA as the result of excessive core valuing of perfectionism and the anxiety it produces because we can see virtually identical, fMRI-visible “hot links” between the same cortical, limbic and brain stem locations.) Similar stress-induced induction of IL-10 expression has been reported for myocardial infarction patients and after traumatic brain injury. Several investigators have documented the exaggerated SNS activation during these periods of critical illness, particularly in patients with head injury. (Well; I just wonder where those head injuries are in a PTSD sufferer: Would they be in the emotion-modulating, neural downlinks to the limbic area from the media pre-frontal and parietal corteces? And would they be microscopic? Would they be "microlesions" at the level of "fried" receptor sites? Would they be demonstrations of chronic over-potentiation or de-potentiation of specific neurosteroidal transferences at synaptic junctions?) Although the detrimental effects of sustained and exaggerated SNS activation on cardiovascular and metabolic homeostasis have been recognized, attention should be brought to the likelihood of immune dysregulation as well. Moreover, the potential immunomodulatory effects of pharmacotherapy used in these critically ill patients needs to be further examined (33).

Thus, sympathoexcitatory pathways exert direct effects on cells of the immune system affecting cytokine expression, lymphocyte function, and cytotoxic activity (Fig. 2). In addition, as described below, the cells of the immune system as well as the inflammatory mediators released by them communicate with the CNS through direct and indirect mechanisms.

THE IMMUNE SYSTEM COMMUNICATES TO THE CNS, FORMING A FEEDBACK LOOP

The neuroimmune bidirectional network is comprised of a descending pathway that links the CNS to peripheral immune tissues and a parallel afferent arm linking the immune system with the CNS. The integrity of this loop allows for communication between the CNS and the peripheral immune system, integrating neuronal and immune signals in the periphery as well as in the CNS. The synaptic-like neural connection with lymphoid tissues modulates multiple cellular processes in the immune system through the local release of neuropeptides, neurotransmitters, and neurohormones. Cells from the immune system express functional receptors and the respective signal-transduction pathway components for several neuroendocrine mediators, allowing cellular functional responses to agonist stimulation. Similarly, cells in the CNS are capable of synthesizing, secreting, and responding to inflammatory and immune-related molecules. There is considerable evidence that the peripheral immune system can signal the brain to elicit a sickness response during infection and inflammation (Fig. 3). Peripheral immune molecules such as cytokines influence CNS actions (34) through various mechanisms, including cytokine entry into the brain through a saturable transport mechanism or through areas that lack the blood-brain barrier as well as through activation of afferent neurons of the vagus nerve. Although active transport is required for some cytokines to enter the brain (35), others gain access into the brain through fenestrated capillaries in different regions of the CNS. These sites are relatively devoid of a blood-brain barrier such as the structures lining the anteroventral border of the third ventricle, including the organum vasculosum of the lateral terminalis and subfornical organ, the median eminence, and the posterior lobe of the pituitary. Their capillaries do not form tight junctions and are thus far more readily penetrable via the paracellular route. Passage of cytokines through these areas is thought to produce localized effects in neuronal structures in the immediate vicinity directly or indirectly (36). Thus, CNS signaling by cytokines may not even require their active transport into the CNS. Signaling may be relayed through classical neurotransmitters or through lipid mediators produced and released in these areas devoid of the blood-brain barrier. Brain microvessels have been shown to respond to cytokine stimulation by producing prostaglandins (PGE2), which can then in turn affect CNS neurotransmission. Other investigators have shown that there is a median eminence site of action at which peripherally stimulated IL-6 possesses CRH-releasing activity. Additionally, evidence suggests that the peripheral production of proinflammatory cytokines may signal the brain through stimulation of vagal afferents (37). Vagal afferent signaling by peripheral immune mediators has been documented to contribute to HPA activation, fever, sleep, norepinephrine turnover, and sickness behavior (38, 39) (so guess what happens if PTSD-type recycling of emotional agitation continues unabated: Would the enteric nervous system in the gut that senses such agitation shoot relentless signaling up the vagus nerve causing the feedback looping of “fight or flight” and turn it into “frying” the dendrites along the entire chain of axonal projections from the amygdala in the limbic system?). The mechanisms involved in the interaction between peripheral cytokines and vagal fibers is still under investigation. Functional cytokine receptors have not been identified in abdominal vagal afferents (aka the enteric nervous system). However, abdominal paraganglia, which are in close proximity to and synapse with vagal fibers, specifically bind biotinylated IL-1ra. Moreover, localized perivagal cytokine production by may also contribute to this signaling mechanism (40). Thus, several mechanisms can be identified that are participant of the signaling from the peripheral immune system to the CNS, closing the bidirectional neuroendocrine loop (precisely as I suggested above).

How these are affected during injury and disease has not been fully investigated. However, several lines of evidence would suggest that pathological conditions would be likely to alter blood-brain barrier permeability, enhancing the access of peripheral immune cells or their products to the CNS (41). This afferent signaling pathway to the CNS in response to peripheral inflammatory challenges functions as a feedback mechanism modulating behavioral and biological responses during disease (Fig. 4). This bidirectional neuroimmune interaction creates a circuit of responses that can be considered an inflammatory reflex because of the immediate effects produced by the release of these neuroendocrine and immune mediators into the periphery, as well as the ability of the CNS of rapidly integrating afferent signals conducted by peripheral nerves. The integrity of such circuit is critical in host protection and adaptation to systemic challenges such as traumatic injury and infection.

RELEVANCE OF THE NEUROIMMUNE REFLEX

Understanding the relevance of neuroimmunomodulation to overall control of inflammatory responses during specific pathological conditions requires a model that resembles a clinical presentation in which the nervous system as well as the immune system are challenged accordingly and in which the outcome from neuroimmune interaction affects the host response. Studies in our laboratory have used hemorrhagic shock in conscious, unrestrained rodents to elucidate the contribution of the SNS to modulation of host response. This model allows for the determination of neuroendocrine activation and the concordant inflammatory response of the host in the absence of anesthetics or sedatives that can alter the efferent neural pathways that are immediately triggered by hypotension and that mediate the restoration of hemodynamic, metabolic, and host defense counterregulatory responses. (I'll suggest here that further research will reveal that over-long proinflammatory response may semi-permanently alter the efferent neural pathways to produce a manifestation of chronic PTSD symptoms.)

Controlled inflammation during a period after injury is essential for tissue repair and maintenance of immune competence (42). The regulated initiation and termination of this tissue proinflammatory response is under neuroendocrine control through direct neurotransmitter release at the target organ, as well as indirectly through humoral factors, including catecholamines, neuropeptides, and glucocorticoids among a few. Although the early post-traumatic inflammatory response is directed to repair tissues and establish immune competence, an increased magnitude and duration of this response is associated with delayed restoration of homeostasis and increased tissue injury leading to multiple organ failure (43) (which seems to agree with the suggested made above).

Several lines of evidence indicate that the early proinflammatory cytokine upregulation contributes to the development of this syndrome by synergistic actions or by priming or predisposing the host to subsequent injury. Thus the pro/anti-inflammatory cytokine balance, which should mediate tissue repair and recovery, if uncontrolled, can produce tissue injury on one spectrum and immunosuppression on the other extreme (44). Hence, the relevance of understanding the mechanisms involved in control of the magnitude and duration of this response.

NEUROIMMUNOMODULATION IN STRESS

The counter-regulatory response to acute and prolonged illness involves the release of catecholamines in high concentrations into the systemic circulation through the sympathoadrenal activation as well as into specific tissue beds through noradrenergic discharge from sympathetic nerve terminals (45). This activation of the SNS is much more evident under conditions of acute traumatic injury, particularly those involving the brain (46) (and it is my observation-based contention that such “acute traumatic injury” includes the microscopic injuries done to neural pathways in the limbic system over time by alcoholism, drug addiction, obsessive hyper-stimulation and/or chronic anxiety). Our working hypothesis is that this sudden and massive release of circulating and tissue catecholamines can affect the magnitude of tissue cytokine response and, consequently, can impact the integrity of subsequent host defense mechanisms. Several clinical observations would support this association. However, demonstration of the role of the SNS in regulation of immune responses during injury is best done in an experimental setting. Using traumatic injury as a trigger for moderate inflammation, we have examined the contribution of tissue norepinephrine content to the inflammatory response after hemorrhagic shock in chronically instrumented conscious unrestrained rodents.

NORADRENERGIC SUPPRESSION OF THE HEMORRHAGE-INDUCED INCREASE IN LUNG TNF

To test the role of tissue norepinephrine, animals were chronically pretreated with small doses of the neurotoxin 6-hyroxy-dopamine (6-OHDA) before hemorrhagic shock (47). Once accumulated in neurons, 6-OHDA undergoes auto-oxidation, causing the degeneration of catecholamine-containing neurons. Enhanced specificity for noradrenergic neurons is achieved through repeated small dose administration. Because 6-OHDA does not penetrate through the blood-brain barrier, the effects of its peripheral administration can be attributed to peripheral noradrenergic nerve endings. Noradrenergic tone was effectively removed by the destruction of noradrenergic nerve terminals (which is pretty much what I see on on scans that seems to occur over time in the limbic tissues as the result of substance and/or behavioral abuse, as well as relentless anxiety), manifested by depletion of norepinephrine stores (80%-90%) in peripheral tissues, including lung and spleen. This removal of tissue norepinephrine stores resulted in an exacerbated rise in lung TNF expression after hemorrhagic shock and fluid resuscitation. These results strongly suggested that during the acute stress produced by hemorrhagic shock, control of the early proinflammatory response is partly under suppressive effects of localized noradrenergic tone. Because norepinephrine is the predominant neurotransmitter released from postganglionic sympathetic nerve terminals, these studies provided evidence of SNS contribution to the regulation of the magnitude of the early proinflammatory response to injury.

Other investigators have reported similar exacerbation of the inflammatory response after liver injury in chemically sympathectomized mice (48). Moreover, studies by Le Tulzo et al. (1) have demonstrated that β-adrenergic blockade increased hemorrhage-induced NF-κB activation and enhanced the hemorrhage-induced proinflammatory cytokine expression in the lung. Evidence supporting a direct anti-inflammatory effect of sympathetic nerve stimulation on cellular responses has been provided by in vitro studies in isolated perfused spleens. In this setting, electrical stimulation of sympathetic nerves inhibits stimulated TNF secretion via β-adrenergic pathways (49). Taken together, these data suggest that overall, tissue norepinephrine exerts anti-inflammatory effects, serving as a brake in the inflammatory cascade, controlling and regulating the magnitude and profile of cytokine responses (but when the limbic system is itself subjected to the excitotoxifying effects of hyper-stimulation over a long period of time, the ANS balance begins to erode, the HPA just "diesels" in epinephrine flood leading to adrenal fatigue syndrome, and there are insufficient amounts of norepinephrine available to “apply the brakes”). Thus, activation of the SNS (autonomous in the case of hemorrhagic shock and stimulated in the case of electrical stimulation) suppresses tissue proinflammatory responses.

The adrenergic effects on immune function appear to be differentially mediated by the specific adrenergic receptor subtypes. The anti-inflammatory effects of norepinephrine appear to be mediated via β2-adrenergic receptors. Le Tulzo et al. (1) showed that although β-blockade enhanced lung proinflammatory cytokine expression, contrasting effects were observed after α-adrenergic antagonist administration before hemorrhagic shock. Their results indicate that α-adrenergic blockade prevents the elevation in mRNA levels of IL-1α, TNF-α, and TGF-β1, the increase in IL-1β protein, as well as the activation of nuclear factor (NF)-κB in intraparenchymal pulmonary mononuclear cells produced by blood loss. Those results suggested that although adrenergic stimulation through the α-adrenergic receptor favored a proinflammatory response, stimulation through the β-adrenergic receptor suppressed or controlled inflammation. This concept of balanced adrenergic control of cytokine production dependent on the specific adrenergic receptor is supported by studies in isolated perfused liver (I have not yet seen studies of the same phenomenon in the limbic system, but see no physiological reason to think it would not exist anywhere else in a body connected to the HPA). In this setting, norepinephrine upregulates TNF production and induces IL-12 through α2-adrenergic receptor-mediated mechanisms (50). These were intriguing findings and their interpretation was complex, as Le Tulzo's (1) studies were performed in anesthetized mice, potentially affecting neural activation during hemorrhage. Furthermore, no assessment was made of the impact of adrenergic blockade on the hemodynamic response to blood loss, a potentially confounding factor to the magnitude of tissue hypoperfusion and thus localized regulation of tissue responses.

Dissecting the contribution of the specific adrenergic receptors involved in modulating proinflammatory responses to hemorrhagic shock is not simple. Results from our studies suggest that the distinction between the adrenergic receptor modulation of tissue cytokine production after hemorrhage can not be clearly demarcated in an in vivo, unanesthetized rodent model of fixed pressure hemorrhage. In vivo administration of adrenergic antagonists can effectively alter the hemodynamic response to blood loss and can affect the severity of the hypotensive response achieved by removal of a given blood volume. Studies from our laboratory show that propranolol pretreatment (1 mg/kg 30 min prehemorrhage) does not produce significant alteration in the tissue expression of TNF, IL-6, and IL1α after hemorrhagic shock and fluid resuscitation. Furthermore, no marked alterations in the hemodynamic response to blood loss and fluid resuscitation were observed in those studies. In contrast, pretreatment with the α-adrenergic receptor antagonist phenoxybenzamine (2.5 mg/kg) before hemorrhagic shock did not produce significant alteration in the magnitude of the tissue cytokine response observed. However, it significantly lowered the blood volume removed required to produce hypotension (mean arterial blood pressure of 40 mmHg). Therefore, α-adrenergic blockade resulted in comparable hemorrhage-induced upregulation in tissue cytokine expression to that elicited by greater blood loss.

Taken together, these results led to the conclusion that depletion of tissue noradrenergic stores removes the inhibitory control on hemorrhage-induced TNF upregulation in the lung. Interestingly, this effect does not appear to be indiscriminate, as no upregulation in IL-6 response was observed in chemically sympathectomized hemorrhaged animals. In contrast, α-adrenergic receptor antagonist-pretreated animals showed an accentuated lung IL-6 response to a given blood loss without affecting the magnitude of the TNF response. Overall, these observations indicate that sympathetic regulation exerts differential adrenergic receptor-mediated effects affecting the balance of cytokine profile expression, supporting a role for sympathetic regulation of immediate tissue cytokine responses to hemorrhagic shock. We speculate that because of the central role of SNS activation during the immediate response to injury, neuroimmune modulation mediated by the SNS during hemorrhagic shock is likely to affect outcome during the postinjury period.

CONCLUSION

SNS activation is central to the integrated stress response. The SNS has significant anatomical and functional interaction with cells of the immune system and plays an important role in control of the magnitude of early inflammatory response to injury by ensuring expression of adequate cytokine balance. These sympathetic neural pathways exert direct effects on cells of the immune system, affecting cytokine expression, lymphocyte function, and cytotoxic activity. In turn, the inflammatory mediators released communicate with the CNS through stimulation of sensory and vagal afferents or by crossing the blood-brain barrier through active transport mechanisms or by taking advantage of areas with fenestrated capillaries, allowing easy access to the median eminence and hypothalamo-pituitary structures. In the CNS, these immune-derived mediators such as cytokines and chemokines modulate neurotransmission, affecting activation of descending autonomic and neuroendocrine pathways. Thus, the system is designed as a neuroendocrine-immune feedback loop in which direct neural activation of lymphoid tissues effects cellular responses, forming a reflex arch, and establishing bidirectional communication.

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